Jian-Guo Chen

Compulsive drug use despite negative consequences is a core addiction feature and key therapeutic target. Animal models utilize footshock to screen for mice exhibiting compulsive-like addiction traits. Following the administration of aversive stimuli, compulsive animals persist in drug-seeking, suggesting that addicted individuals may have impaired innate defensive responses, thereby exacerbating addictive behaviors. However, little is known about the neural mechanisms behind this behavior. The superior colliculus (SC), a multisensory integration hub, plays a crucial regulatory role in innate fear and defense. This study employed an optical intracranial self-stimulation (oICSS) addiction-like model. Using footshock to screen for mice with compulsive-like behavior, fiber photometry recordings revealed significant differences in neuronal activity within the SC. Specifically, SC neurons in compulsive-like mice showed significantly lower responses to footshock stimuli compared to non-compulsive mice. Subsequently, chemogenetic inhibition of SC neuronal activity in non-compulsive mice significantly reduced their resistance to footshock, inducing a compulsive-like state. Conversely, chemogenetic activation of SC neurons in compulsive-like mice significantly decreased their oICSS behavior. These findings indicate that mice exhibiting compulsive-like addiction behavior, identified through footshock, exhibit significant functional abnormalities in SC neurons. The SC is implicated in regulating compulsive addictive behaviors, providing novel insights into the mechanisms of compulsivity and identifying a promising new target for addiction intervention.

Chronic stress can trigger major depressive disorder through peripheral immune factors. Enhanced circulating levels of complement component 3 (C3), a key innate immunity molecule that is predominantly produced by the liver, have been observed in depressed patients. However, the role of liver-derived C3 in the regulation of behavior under chronic stress remains ambiguous. Here, we found that liver-derived C3 critically contributes to stress susceptibility and blood-brain barrier (BBB) impairment in the nucleus accumbens (NAc) by inhibiting endothelial cell claudin-5, a pivotal tight junction protein for BBB integrity. In three mouse models of depression, hepatic C3 expression was notably increased in mice, with no comparable changes in other peripheral organs. Genetic ablation of C3 ameliorated chronic social defeat stress (CSDS)-induced increases in NAc BBB permeability and depressive-like behavior, and this amelioration was reversed upon re-expression of hepatic C3. Consistently, knockdown of hepatic C3 similarly improved these deleterious effects induced by CSDS. Furthermore, overexpression of hepatic C3 was sufficient to induce depressive-like behavior following subthreshold social stress. Hepatic C3 manipulation bidirectionally regulated expression of claudin-5 in NAc endothelial cells. Mechanistically, the liver-derived C3 suppressed claudin-5 expression in brain endothelial cells and increased stress susceptibility in mice through the C3a receptor-CCAAT/enhancer-binding protein-α signaling pathway in the NAc. Moreover, corticosterone upregulated hepatic C3 release by activation of nuclear factor-κB (NF-κB). Taken together, these results demonstrate that liver-derived C3 promotes susceptibility to depression by increasing BBB permeability under chronic stress, and propose targeting hepatic C3 as a promising therapeutic strategy for depression.

Dysfunction of parvalbumin-expressing interneurons (PV-INs) in the cerebral cortex has been implicated in major depressive disorder. Perineuronal nets (PNNs), which encapsulate PV-INs, are considered to influence the structural and functional properties of PV-INs. Semaphorin 3A (Sema3A) is a secreted protein constituent of PNNs, but the specific roles of Sema3A in modulating PV-INs during stress remain unknown. Here, we demonstrated that Sema3A, secreted by GABAergic interneurons, contributed to the response to chronic stress in male mice. The accumulation of Sema3A interacts with PNNs and facilitates PNNs wrapping of PV-INs, leading to a decrease in inhibitory synaptic input and an increase in the excitability of PV-INs. Sema3A-mediated formation of PNNs and the subsequent increase in PV-INs excitability may promote the development of depressive-like behaviors induced by stress. These results elucidate a molecular pathway in which Sema3A, a component of PNNs, dynamically governs the function of PV-INs to facilitate adaptive behavioral responses to stress.

Rationale: Depression is commonly comorbid with cancer and affects therapeutic efficacy and outcome-of-disease. However, the molecular mechanism underlying cancer-induced depression (CID) remains poorly understood. Twist1 is a proto-oncogene driving tumor progression and metastasis, and chronic stress induces Twist1 expression in the medial prefrontal cortex (mPFC). This study aims to investigate the role and mechanisms of tumor-derived Twist1 in CID.

While Virtual Reality (VR) technology shows promise in the management of substance use disorders, the development of an effective VR-based extinction procedure remains lacking. In this study, we developed a VR-based eye movement desensitization and reprocessing extinction training program tailored for mice. We found that this VR treatment during cocaine extinction prevents reinstatement by suppressing the hyperactivation of glutamatergic excitatory neurons in the intermediate layers of the superior colliculus (SCiCaMKIIα) during exposure to environmental cues. Additionally, SCiCaMKIIα neurons innervate tyrosine hydroxylase-positive neurons in the locus coeruleus (LCTH). Environmental cues trigger stronger phasic activation of LCTH neurons through this SCiCaMKIIα→LCTH projection, leading to increased dopamine release onto the dorsal CA3 (dCA3) region, thereby facilitating reinstatement. Furthermore, we demonstrate that VR treatment effectively inhibits the neural circuitry involving SCiCaMKIIα→LCTH→dCA3 in response to environmental cues, thus preventing cocaine reinstatement. Our findings suggest that VR treatment may represent a promising strategy for achieving drug abstinence.

Melatonin (N‐acetyl‐5‐methoxytryptamine) is reported to improve mood disorders in perimenopausal women and gut microbiome composition is altered during menopausal period. The possible role of microbiome in the treatment effect of melatonin on menopausal depression remains unknown. Here, it is shown that melatonin treatment reverses the gut microbiota dysbiosis and depressive‐like behaviors in ovariectomy (OVX) operated mice. This effect of melatonin is prevented by antibiotic cocktails (ABX) treatment. Transferring microbiota harvested from adolescent female mice to OVX‐operated mice is sufficient to ameliorate depressive‐like behaviors. Conversely, microbiota transplantation from OVX‐operated mice or melatonin‐treated OVX‐operated mice to naïve recipient mice exhibits similar phenotypes to donors. The colonization of Alistipes Inops, which is abundant in OVX‐operated mice, confers the recipient with depressive‐like behaviors. Further investigation indicates that the expansion of Alistipes Inops induced by OVX leads to the degradation of intestinal tryptophan, which destroys systemic tryptophan availability. Melatonin supplementation restores systemic tryptophan metabolic disorders by suppressing the growth of Alistipes Inops, which ameliorates depressive‐like behaviors. These results highlight the previously unrecognized role of Alistipes Inops in the modulation of OVX‐induced behavioral disorders and suggest that the application of melatonin to inhibit Alistipes Inops may serve as a potential strategy for preventing menopausal depressive symptoms.